High SHBG, Low free T.

Csd456 · Friday at 9:14 AM

I’ve had low T symptoms for around 4 years now. Libido, morning erection, hard gainer, increased fatty tissue, lacking drive etc.

SHBG between 80-100 ish
Free T around 0.25 nmol/L

I’m 34, fit and heathly. Lift 4 times per week, decent diet, cardio 2-3 times per week. 170lbs 5’9”

I’ve seen a couple of endos who basically shrug shoulders and offer the blue pill!

I’m reluctant to hop on TRT because my system is working, I’m also hoping to get my other half pregnant soon.

I’ve considered proviron, but chickened out before taking any.

Any last suggestions before going on the TRT route? Should I get a more detailed thyroid panel for example, even though it all seems be be within the reference ranges from my tests so far.

Blood work below (I hope the table has formatted correctly) for the last year. But I have results going back 4 years that basically show the same story.

I’ve read this forum back to front, so I’m just clutching at straws really. Thanks all.

		16 Feb 2024	20 July 2024	5 Sep 2024	9 Oct 2024	6 Nov 2024	7 Jan 2025	7 Apr 2025

FSH	1.5-12.4 IU/L	3.1	2.8	2.6	3.4	3.3	2.8	3
LH	1.7-8.6 IU/L	4	2.7	3.5	4.1	2.8	3.1	3.6
Oestrodiol	41-159 pmol/L	120	106	47.1	90	54.7	85.6	68.2
Testosterone	8.64-29 nmol/L	30	23.7	19.1	25.3	26.1	29.4	22.1
Free test Calc.	0.2-0.62 nmol/L	0.362	0.3	0.177	0.284	0.23	0.269	0.241
T:Cortisol	Ratio		0.065	0.03
Free androgen	Index 35-92%		34.1	19.8			28
Prolactin	86-324 mIU/L	136	181	279	213	201		312

PSA Total	<2.6 ug/L	0.518			0.435	0.645		0.43

Haemoglobin	130-180 g/L	141	144	142	135	149	153	150
Haematocrit	0.4-0.52 L/L	0.421	0.438	0.433	0.404	0.439	0.455	0.445
Red Cell Count	4.4-6.5 10^12/L	4.38	4.51	4.41	4.1	4.59	4.67	4.52
MCV	80-100 fL	96.1	97	98.3	98.4	95.7	97.4	98.4
MCH	27-32 pg	32.1	32	32.2	32.8	32.4	32.8	33.3
MCHC	320-360 g/L	334	330	327	333	339	336	338
RDW	11.5-15 %	13.5	15.3	14.1	14.1	13.2	14.6	14
White cell count	3-11 10^9/L	3.9	3.1	4.5	3.2	4.5	4.3	4.3
Neutrophils	2-7.5 10^9/L	1.6	1.1	1.9	0.9	1.5	1.5	1.2
Lymphocytes	1.5-4.5 10^9/L	1.6	1.5	2	1.6	2.2	2.4	2.4
Monocytes	0.2 - 0.8 10^9/L	0.4	0.3	0.4	0.3	0.4	0.2	0.4
Eosinophils	0 - 0.4 10^9/L	0.3	0.2	0.2	0.2	0.2	0.2	0.3
Basophils	0 - 0.1 10^9/L	0.1	0	0	0	0.1	0	0
Platelet Count	150 - 450	213	216	185	215	268	226	211
MPV	7-13		10.7	12.1	11.5	11.3	11.3	11.3

Creatinine	60 - 120 umol/L	85.9	83.2	86.9	92.6	92.6	90	80
eGFR	>60	>90	90	>90	>90	>90	>90	>90
Urea	2.5-7.8 mmol/L		5.5	7.2			8.9

Bilirubin	<22 umol/L	11.4	19	10.9	10.8	12.8	14	8
ALP	30 - 130 U/L	48	56	53	52	58	56	67
ALT	<45 U/L	24	17	23	31	26	35	29
GGT	<55 U/L	20	16	16	19	19	23	19

Total Protein	60 - 80 g/L	68	70	69	69	72	71	72
Albumin	35 - 50 g/L	46	48	48	49	50	50	49
Globulin	19 - 35 g/L	21	23	21	20	22	22	23
SHBG	18.3 - 54.1 nmol/L	79.4	69.4	96.7	80.9	107	105	81.4

HbA1c	20 - 41.999 mMol/Mol	26	32	29	26	28	25	24

Total Cholesterol	<5 mmol/L	6.5	5.74	5.34	5.54	5.21	5.3	6.65
LDL	<3 mmol/L	3.49	3.04	2.78	2.85	3.07	2.79	3.87
Non HDL	<4 mmol/L	3.81	3.47	3.18	3.26	3.46	3.2	4.22
HDL	>1 mmol/L	2.69	2.27	2.16	2.28	1.75	2.1	2.43
Total : HDL	<6 ratio	2.42	2.53	2.47	2.43	2.98	2.52	2.74
Triglycerides	<2.3 mmol/L	0.71	0.95	0.88	0.91	0.85	0.9	0.77
Triglycerides:HDL	<.87 ratio						0.4
Apolipoprotein A1	>1.25 g/L						1.7
Apolipoprotein B	<1 g/L						0.96
Lipoprotein A	<76 nmol/L						51.1
APOB:APOA	,0.7 ratio						0.6

CRP HS	0-3 mg/L		0.897	<0.15			0.29

Utica Acid	200-430 umol/L		314	282			245

Iron	10-30 umol/L		28.5	17.5
TIBC	45-81 umol/L		55.9	51.6
UIBC	12-43 umol/L		27.4	34.1
Transferrin Sat.	25-45%		51	33.9
Ferritin	30 - 442 ug/L	104	180	127	67.5	138	110	198

TSH	0.27 - 4.2 mIU/L	1.82	2.15	2.55	2.1	2.39	3.25	3.13
Free T3	3.1 - 6.8 pmol/L	3.5	3.4	3.4	3.9	3.3	3.4	3.4
Free Thyroxine	12 - 22 pmol/L	15.9	16.9	15.7	17.3	19.3	15.7	18.6

Folate Serum	7-35 nmol/L		15.1	7.4
B12 active	37.5-188 pmol/L		150	115			>150
Vit D	50-250 nmol/L		96.8	111			180

DHEA Sulphate	4.34-12.2	4.3	5	4.3
Cortisol	133-537		365	502

Thyroglobulin	<115 kIU/L		17.3	15.7			15.7
Thyroid peroxidase	<9 kIU/L		9	10.2			<9

Cataceous · Friday at 10:46 AM

Csd456 said:
...
I’m reluctant to hop on TRT because my system is working, I’m also hoping to get my other half pregnant soon.
...

Your free testosterone isn't extremely low, so it's borderline whether you should be characterized as hypogonadal. Nonetheless, there are at least some suggestions that very high SHBG like yours may interfere with androgenic activity. Therefore I wouldn't condemn you for wanting to experiment. It's good that you have some awareness of the possible negative consequences of traditional TRT. Fortunately there are alternatives.

There are two options that might be called TRT-lite: either testosterone nasal gel (e.g. Natesto) or buccal testosterone troches. These are very fast acting forms of testosterone, meaning that after a dose serum testosterone does not stay elevated for more than a few hours. This allows your system to keep working normally, and generally preserves fertility. In contrast, traditional TRT is relatively long acting and usually results in complete HPTA suppression.

Another option is to use a SERM such as enclomiphene. This can be quite effective in improving free testosterone. However, there are mixed anecdotes concerning the subjective benefits.

If none of these options is practical for you then I'll throw out the unproven possibility that some forms of testosterone suspension may qualify as "short-acting", and thus could behave like nasal gel or buccal troches. The main drawback is that this requires two or three small injections daily. On the plus side, at least in the U.S. it is not difficult to obtain testosterone suspension.

Systemlord · Friday at 11:03 AM

Csd456 said:
Any last suggestions before going on the TRT route? Should I get a more detailed thyroid panel for example, even though it all seems be be within the reference ranges from my tests so far.

Thyroid problems would present with low SHBG.

Do you cut/starve yourself to look ripped?

If so this can raise SHBG and lower testosterone production.

Csd456 said:
I’m reluctant to hop on TRT because my system is working

This statement makes no sense. You can have a functioning HPTA and feel like normal everyday actively is akin to climbing Mount Everest.

Quality of life is all that matters.

madman · Friday at 11:16 AM

Csd456 said:
I’ve had low T symptoms for around 4 years now. Libido, morning erection, hard gainer, increased fatty tissue, lacking drive etc.

SHBG between 80-100 ish
Free T around 0.25 nmol/L

I’m 34, fit and heathly. Lift 4 times per week, decent diet, cardio 2-3 times per week. 170lbs 5’9”

I’ve seen a couple of endos who basically shrug shoulders and offer the blue pill!

I’m reluctant to hop on TRT because my system is working, I’m also hoping to get my other half pregnant soon.

I’ve considered proviron, but chickened out before taking any.

Any last suggestions before going on the TRT route? Should I get a more detailed thyroid panel for example, even though it all seems be be within the reference ranges from my tests so far.

Blood work below (I hope the table has formatted correctly) for the last year. But I have results going back 4 years that basically show the same story.

I’ve read this forum back to front, so I’m just clutching at straws really. Thanks all.

16 Feb 2024
20 July 2024
5 Sep 2024
9 Oct 2024
6 Nov 2024
7 Jan 2025
7 Apr 2025
FSH
1.5-12.4 IU/L

3.1
2.8
2.6
3.4
3.3
2.8
3
LH
1.7-8.6 IU/L

4
2.7
3.5
4.1
2.8
3.1
3.6
Oestrodiol
41-159 pmol/L

120
106
47.1
90
54.7
85.6
68.2
Testosterone
8.64-29 nmol/L

30
23.7
19.1
25.3
26.1
29.4
22.1
Free test Calc.
0.2-0.62 nmol/L

0.362
0.3
0.177
0.284
0.23
0.269
0.241
T:Cortisol
Ratio

0.065
0.03
Free androgen
Index 35-92%

34.1
19.8
28
Prolactin
86-324 mIU/L

136
181
279
213
201
312
PSA Total
<2.6 ug/L

0.518
0.435
0.645
0.43
Haemoglobin
130-180 g/L

141
144
142
135
149
153
150
Haematocrit
0.4-0.52 L/L

0.421
0.438
0.433
0.404
0.439
0.455
0.445
Red Cell Count
4.4-6.5 10^12/L

4.38
4.51
4.41
4.1
4.59
4.67
4.52
MCV
80-100 fL

96.1
97
98.3
98.4
95.7
97.4
98.4
MCH
27-32 pg

32.1
32
32.2
32.8
32.4
32.8
33.3
MCHC
320-360 g/L

334
330
327
333
339
336
338
RDW
11.5-15 %

13.5
15.3
14.1
14.1
13.2
14.6
14
White cell count
3-11 10^9/L

3.9
3.1
4.5
3.2
4.5
4.3
4.3
Neutrophils
2-7.5 10^9/L

1.6
1.1
1.9
0.9
1.5
1.5
1.2
Lymphocytes
1.5-4.5 10^9/L

1.6
1.5
2
1.6
2.2
2.4
2.4
Monocytes
0.2 - 0.8 10^9/L

0.4
0.3
0.4
0.3
0.4
0.2
0.4
Eosinophils
0 - 0.4 10^9/L

0.3
0.2
0.2
0.2
0.2
0.2
0.3
Basophils
0 - 0.1 10^9/L

0.1
0
0
0
0.1
0
0
Platelet Count
150 - 450

213
216
185
215
268
226
211
MPV
7-13

10.7
12.1
11.5
11.3
11.3
11.3
Creatinine
60 - 120 umol/L

85.9
83.2
86.9
92.6
92.6
90
80
eGFR
>60

>90
90
>90
>90
>90

>90
>90
Urea
2.5-7.8 mmol/L

5.5
7.2
8.9
Bilirubin
<22 umol/L

11.4
19
10.9
10.8
12.8
14
8
ALP
30 - 130 U/L

48
56
53
52
58
56
67
ALT
<45 U/L

24
17
23
31
26
35
29
GGT
<55 U/L

20
16
16
19
19
23
19
Total Protein
60 - 80 g/L

68
70
69
69
72
71
72
Albumin
35 - 50 g/L

46
48
48
49
50
50
49
Globulin
19 - 35 g/L

21
23
21
20
22
22
23
SHBG
18.3 - 54.1 nmol/L

79.4
69.4
96.7
80.9
107
105
81.4
HbA1c
20 - 41.999 mMol/Mol

26
32
29
26
28
25
24
Total Cholesterol
<5 mmol/L

6.5
5.74
5.34
5.54
5.21
5.3
6.65
LDL
<3 mmol/L

3.49
3.04
2.78
2.85
3.07
2.79
3.87
Non HDL
<4 mmol/L

3.81
3.47
3.18
3.26
3.46
3.2
4.22
HDL
>1 mmol/L

2.69
2.27
2.16
2.28
1.75
2.1
2.43
Total : HDL
<6 ratio

2.42
2.53
2.47
2.43
2.98
2.52
2.74
Triglycerides
<2.3 mmol/L

0.71
0.95
0.88
0.91
0.85
0.9
0.77
Triglycerides:HDL
<.87 ratio

0.4
Apolipoprotein A1
>1.25 g/L

1.7
Apolipoprotein B
<1 g/L

0.96
Lipoprotein A
<76 nmol/L

51.1
APOB:APOA
,0.7 ratio

0.6
CRP HS
0-3 mg/L

0.897
<0.15
0.29
Utica Acid
200-430 umol/L

314
282
245
Iron
10-30 umol/L

28.5
17.5
TIBC
45-81 umol/L

55.9
51.6
UIBC
12-43 umol/L

27.4
34.1
Transferrin Sat.
25-45%

51
33.9
Ferritin
30 - 442 ug/L

104
180
127
67.5
138
110
198
TSH
0.27 - 4.2 mIU/L

1.82
2.15
2.55
2.1
2.39
3.25
3.13
Free T3
3.1 - 6.8 pmol/L

3.5
3.4
3.4
3.9
3.3
3.4
3.4
Free Thyroxine
12 - 22 pmol/L

15.9
16.9
15.7
17.3
19.3
15.7
18.6
Folate Serum
7-35 nmol/L

15.1
7.4
B12 active
37.5-188 pmol/L

150
115
>150
Vit D
50-250 nmol/L

96.8
111
180
DHEA Sulphate
4.34-12.2

4.3
5
4.3
Cortisol
133-537

365
502
Thyroglobulin
<115 kIU/L

17.3
15.7
15.7
Thyroid peroxidase
<9 kIU/L

9
10.2
<9

Unfortunately a common scenario misunderstood by many doctors where they are caught up on TT when FT is what truly matters.

The TT is inflated due to very high SHBG which would result in a bottom-end FT!

Just to clear up any confusion here keep in mind that the bound fractions albumin/SHBG still serve a purpose and are not useless binding proteins as many stinking up all those so called HRT/men's health forums let alone those so called gurus polluting the net!

As has been stated numerous times on the forum over the years although TT is important to know FT is what truly matters as it is the unbound fraction of T responsible for the positive effects.

Free testosterone and its metabolites estradiol and DHT are where it's at!

In order to know where your free testosterone truly sits one would need to have it tested using what would be considered the most accurate assay the gold standard Equilibrium Dialysis especially in cases of altered SHBG!

f you do not have access (highly doubtful if you reside in the US) to such then you would need to use/rely upon the go to calculated linear law-of-mass action cFTV which will give a good approximation but keep in mind it tends to overestimate FT.

As I have stated numerous times on the forum you always have the option of using/relying upon calculated FT which would be the linear law-of-mass action cFTV as it has already been validated twice (1st time was done using TT/SHBG assays no longer available) and was then eventually re-validated using current state-of-the-art ED method (higher order reference method) let alone more recently against CDCs standardized Equilibrium Dialysis assay.

Yes it tends to overestimate slightly but it is nothing to fret over!

*Calculated free T using high-quality T and SHBG assays has been considered the most useful for clinical purposes [99]. All algorithms suffer from some inaccuracies, including the variable quality of SHBG IAs [100], not replicating the non-linear nature of T-SHBG binding, different and inaccurate association constants for SHBG and albumin binding [101], and variable agreement with equilibrium dialysis results [99,100]. However, until further developments in the field materialize, the linear model algorithms [in particular, the most used Vermeulen equation [102]] appear to give, despite a small systematic positive bias, acceptable data for the clinical management and research[37,103]

Thread 'Use of calculated FT in men: advantages and limitations'

Nov 6, 2024

Use of calculated free testosterone in men: advantages and... : Current Opinion in Endocrinology, Diabetes and Obesity

hting its relevance in preventing misdiagnosis and overtreatment of male hypogonadism. Recent findings While there is consensus on measuring total T – comprising sex hormone-binding globulin (SHBG)-bound, albumin-bound, and free T – as a first step in diagnosing male hypogonadism, evidence...

journals.lww.com

INTRODUCTION

Clinical practice guidelines on the diagnosis of male hypogonadism focus on clinical signs and symptoms of androgen deficiency, as well as biochemical assessment of low circulating testosterone (T). However, there is a longstanding debate, as well as a persisting controversy concerning biochemical assessment of serum T and in particular the use (and misuse) of free T. Free T, as advocated by the free hormone hypothesis, represents...

Looking over your most recent labs Jan/April 7th if we take your TT, SHBG and Albumin and use the calculated linear law-of-mass action Vermeulen (cFTV) your free testosterone would fall in the bottom-end seeing as although you are hitting a robust TT your SHBG is absurdly high!

Your CFTV results were 7.76 and 6.94 ng/dL.

Also keep in mind that cFTV tends to overestimate slightly so chances are where your FT truly sits is even lower!

A FT 5 ng/dL is low and 5-9 ng/dL would be the grey zone for some!

Most healthy young males would be hitting a cFTV 13-15 ng/dL and this is a daily short-lived peak to boot!

Trough would be 20-25% lower!

Your FT is well under where a healthy young male would sit!

Free & Bioavailable Testosterone calculator

Jan.7/2025

Apr.7/2025

Not sure why you are so concerned about hopping on TTh as even though it will result in shut-down of the hpta and have have a negative impact on fertility you can easily minimize/prevent this from happening through the addition of hCG which mimics LH.

LH stimulates the Leydig cells in the testes to produce ITT (intratesticular testosterone) and ITT/FSH stimulates the Sertoli/germ cells located inside the seminiferous tubule lobes to produce sperm.

When one uses exogenous testosterone/AAS it results in shut down of the HPG axis and the pituitary no longer secretes LH/FSH.

Lack of LH causes atrophy of the Leydig cells which are located between the seminiferous tubules and lack of ITT/FSH causes atrophy of the Sertoli/germ cells which are located inside the seminiferous tubules. The cells shrink and become dormant.

The body no longer produces endogenous testosterone and sperm production is halted.

The Leydig cells only make up 10-20% of testicular volume as oppose to the germ cells/seminiferous tubules (where sperm is produced) which make up almost 80% of the testicular volume so a majority of the shrinkage results from atrophy of the germ cells/seminiferous tubules.

Basically comes down to exogenous testosterone use results in significant suppression of spermatogenesis which leads to testicular shrinkage as a majority of testes volume is made up of germ cells located in the tightly bundled seminiferous tubule lobes where sperm is produced.

Not only does FSH stimulate sperm production but ITT alone is also playing a strong role.

Regarding the use of hCG we can take it along with trt to maintain fertility/prevent testicular shrinkage.

The use of hCG will mimic LH and result in stimulating the Leydig cells in the testes to produce ITT which will have a big impact on stimulating the Sertoli/germ cells located inside the seminiferous tubule lobes to produce sperm and this will cause an increase in testicular volume.

The use of Clomid stimulates LH and FSH which will increase testosterone/sperm production and maintain testicular size.

Look over the threads in post # 3!

Thread 'T in Prostate Cancer, in Combination with GH Secretagogues, and in Fertility - Dr. Lipshultz'

Apr 7, 2025

Bringing you the latest and greatest!

Nelson's house is where it's at!

15:47-17:57 (T levels on therapy/sides)

* The right answer is you've got to keep testosterone within the normal range which is 200/300-1000 ng/dL but its very hard to do and make the patient feel well, they will feel better in the higher-end of that regimen rather than the lower-end

In this episode, Dr. Amy Pearlman interviews Dr. Larry lipshultz, one of the most prolific and well known hormone specialists in the world. He is Professor of Urology and Chief of...

madman · 2025-04-13T10:48:07-0500

madman said:
Unfortunately a common scenario misunderstood by many doctors where they are caught up on TT when FT is what truly matters.

The TT is inflated due to very high SHBG which would result in a bottom-end FT!

Just to clear up any confusion here keep in mind that the bound fractions albumin/SHBG still serve a purpose and are not useless binding proteins as many stinking up all those so called HRT/men's health forums let alone those so called gurus polluting the net!

As has been stated numerous times on the forum over the years although TT is important to know FT is what truly matters as it is the unbound fraction of T responsible for the positive effects.

Free testosterone and its metabolites estradiol and DHT are where it's at!

In order to know where your free testosterone truly sits one would need to have it tested using what would be considered the most accurate assay the gold standard Equilibrium Dialysis especially in cases of altered SHBG!

f you do not have access (highly doubtful if you reside in the US) to such then you would need to use/rely upon the go to calculated linear law-of-mass action cFTV which will give a good approximation but keep in mind it tends to overestimate FT.

As I have stated numerous times on the forum you always have the option of using/relying upon calculated FT which would be the linear law-of-mass action cFTV as it has already been validated twice (1st time was done using TT/SHBG assays no longer available) and was then eventually re-validated using current state-of-the-art ED method (higher order reference method) let alone more recently against CDCs standardized Equilibrium Dialysis assay.

Yes it tends to overestimate slightly but it is nothing to fret over!

*Calculated free T using high-quality T and SHBG assays has been considered the most useful for clinical purposes [99]. All algorithms suffer from some inaccuracies, including the variable quality of SHBG IAs [100], not replicating the non-linear nature of T-SHBG binding, different and inaccurate association constants for SHBG and albumin binding [101], and variable agreement with equilibrium dialysis results [99,100]. However, until further developments in the field materialize, the linear model algorithms [in particular, the most used Vermeulen equation [102]] appear to give, despite a small systematic positive bias, acceptable data for the clinical management and research[37,103]

Thread 'Use of calculated FT in men: advantages and limitations'

Nov 6, 2024

Use of calculated free testosterone in men: advantages and... : Current Opinion in Endocrinology, Diabetes and Obesity

hting its relevance in preventing misdiagnosis and overtreatment of male hypogonadism. Recent findings While there is consensus on measuring total T – comprising sex hormone-binding globulin (SHBG)-bound, albumin-bound, and free T – as a first step in diagnosing male hypogonadism, evidence...

journals.lww.com

INTRODUCTION

Clinical practice guidelines on the diagnosis of male hypogonadism focus on clinical signs and symptoms of androgen deficiency, as well as biochemical assessment of low circulating testosterone (T). However, there is a longstanding debate, as well as a persisting controversy concerning biochemical assessment of serum T and in particular the use (and misuse) of free T. Free T, as advocated by the free hormone hypothesis, represents...

madman

hypogonadism; free testosterone; cft/ed

Replies: 10

Forum: Testosterone and Men's Health Articles

Looking over your most recent labs Jan/April 7th if we take your TT, SHBG and Albumin and use the calculated linear law-of-mass action Vermeulen (cFTV) your free testosterone would fall in the bottom-end seeing as although you are hitting a robust TT your SHBG is absurdly high!

Your CFTV results were 7.76 and 6.94 ng/dL.

Also keep in mind that cFTV tends to overestimate slightly so chances are where your FT truly sits is even lower!

A FT 5 ng/dL is low and 5-9 ng/dL would be the grey zone for some!

Most healthy young males would be hitting a cFTV 13-15 ng/dL and this is a daily short-lived peak to boot!

Trough would be 20-25% lower!

Your FT is well under where a healthy young male would sit!

Free & Bioavailable Testosterone calculator

Jan.7/2025
View attachment 51324

Apr.7/2025
View attachment 51325

Not sure why you are so concerned about hopping on TTh as even though it will result in shut-down of the hpta and have have a negative impact on fertility you can easily minimize/prevent this from happening through the addition of hCG which mimics LH.

LH stimulates the Leydig cells in the testes to produce ITT (intratesticular testosterone) and ITT/FSH stimulates the Sertoli/germ cells located inside the seminiferous tubule lobes to produce sperm.

When one uses exogenous testosterone/AAS it results in shut down of the HPG axis and the pituitary no longer secretes LH/FSH.

Lack of LH causes atrophy of the Leydig cells which are located between the seminiferous tubules and lack of ITT/FSH causes atrophy of the Sertoli/germ cells which are located inside the seminiferous tubules. The cells shrink and become dormant.

The body no longer produces endogenous testosterone and sperm production is halted.

The Leydig cells only make up 10-20% of testicular volume as oppose to the germ cells/seminiferous tubules (where sperm is produced) which make up almost 80% of the testicular volume so a majority of the shrinkage results from atrophy of the germ cells/seminiferous tubules.

Basically comes down to exogenous testosterone use results in significant suppression of spermatogenesis which leads to testicular shrinkage as a majority of testes volume is made up of germ cells located in the tightly bundled seminiferous tubule lobes where sperm is produced.

Not only does FSH stimulate sperm production but ITT alone is also playing a strong role.

Regarding the use of hCG we can take it along with trt to maintain fertility/prevent testicular shrinkage.

The use of hCG will mimic LH and result in stimulating the Leydig cells in the testes to produce ITT which will have a big impact on stimulating the Sertoli/germ cells located inside the seminiferous tubule lobes to produce sperm and this will cause an increase in testicular volume.

The use of Clomid stimulates LH and FSH which will increase testosterone/sperm production and maintain testicular size.

Look over the threads in post # 3!

Thread 'T in Prostate Cancer, in Combination with GH Secretagogues, and in Fertility - Dr. Lipshultz'

Apr 7, 2025

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15:47-17:57 (T levels on therapy/sides)

* The right answer is you've got to keep testosterone within the normal range which is 200/300-1000 ng/dL but its very hard to do and make the patient feel well, they will feel better in the higher-end of that regimen rather than the lower-end

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In this episode, Dr. Amy Pearlman interviews Dr. Larry lipshultz, one of the most prolific and well known hormone specialists in the world. He is Professor of Urology and Chief of...

madman

hypogonadism; testosterone; pca; fertility: gh

Replies: 3

Forum: Prostate Related Issues

Critical points here!

* In men, the SHBG concentration is 30–50% of the female concentration. In healthy men with an intact hypothalamic pituitary-gonadal axis, an increase in SHBG plasma levels leads to a short-term reduction in free testosterone while stimulating testosterone synthesis until normal levels are restored. Both an increase and a decrease in SHBG levels can be regulated by this feedback mechanism.

* SHBG has a central function in the regulation of free testosterone

* The dissociation of testosterone from the binding protein occurs in capillaries. There, an interaction of the binding proteins with the endothelial glycocalyx occurs, which leads to a conformational change of the proteins in the hormone binding site and thus to a change in affinity. Testosterone is subsequently released and can diffuse into the target cell. Thus, SHBG has a central function in the regulation of free testosterone. Steroids can reach their destinations in different ways. Either directly through the membrane as free steroid or bound to a steroid carrier molecule via a membrane-bound receptor. The entire complex can be actively taken up by endocytosis at the LDL molecule, as in the case of the megalin protein, or introduced into the cell via a steroid channel (Hammes et al. 2005). Megalin is expressed in the target organs of sexual steroids and is also a member of the LDL superfamily of endocytotic proteins. In serum 98–99.5% ofthe sex hormones are bound to protein. Compared to the free diffusion of biologically active hormones, endocytotic uptake plays a far more important role in the transport to the target organs.

Physiology of Testicular Function
Joachim Wistuba, Nina Neuhaus, and Eberhard Nieschlag

2.1.5.2 Transport of Testosterone in Blood

In plasma, testosterone is transported predominantly in a bound state. Two proteins are of particular importance here, albumin and sex hormone-binding globulin (SHBG), a βglobulin consisting of nonidentical protein subunits. The synthesis site is the testis and the liver. Plasma SHBG has a molecular weight of 95 kDa, has a high proportion (30%) of carbohydrates and has one androgen-binding site per molecule. A similar protein, namely androgen-binding protein (ABP), is secreted in the testis and was first described in rats and rabbits, in which it serves as the only binding partner for androgens as SHBG is missing in these species. Germ cells also express SHBG in the testis, but this is about 4–5 kDa smaller than the plasma SHBG. This second SHBG isoform is characterized by strongly reduced androgen-binding capacity (Selva et al. 2005). Plasma SHBG is expressed by Sertoli cells and is mainly taken up via the tubules in the caput epididymis by epithelial cells, which regulate maturation of the spermatozoa that pass through the isoform in an androgen-dependent manner. During this maturation, the sperm contain testicular SHBG, which is released afterwards during the capacitation reaction.

In men, 2% of testosterone is normally present in the blood unbound (free testosterone), while 44% is bound to SHBG, and 54% to albumin. Interestingly, the binding affinity of albumin is about 100 times lower than that of SHBG. However, due to the high albumin concentration in the plasma, the absolute binding capacities for both proteins are about the same. The ratio of SHBG-bound testosterone to free SHBG is proportional to the SHBG concentration. As direct determination of the free testosterone content in serum is difficult, this value is calculated from the total testosterone value.

The dissociation of testosterone from the binding protein occurs in capillaries. There, an interaction of the binding proteins with the endothelial glycocalyx occurs, which leads to a conformational change of the proteins in the hormone binding site and thus to a change in affinity. Testosterone is subsequently released and can diffuse into the target cell. Thus, SHBG has a central function in the regulation of free testosterone. Steroids can reach their destinations in different ways. Either directly through the membrane as free steroid or bound to a steroid carrier molecule via a membrane-bound receptor. The entire complex can be actively taken up by endocytosis at the LDL molecule, as in the case of the megalin protein, or introduced into the cell via a steroid channel (Hammes et al. 2005). Megalin is expressed in the target organs of sexual steroids and is also a member of the LDL superfamily of endocytotic proteins. In serum 98–99.5% ofthe sex hormones are bound to protein. Compared to the free diffusion of biologically active hormones, endocytotic uptake plays a far more important role in the transport to the target organs.

SHBG is also capable of binding estradiol, hence the alternate name “Testosterone-Estradiol-Binding Globulin(TeBG).” However, this binding is influenced by various isoforms of SHBG and testosterone binds approximately three times more strongly than estradiol. Post-translational changes in the carbohydrate composition of SHBG can modulate the protein’s binding affinities to testosterone and estradiol. The concentration of SHBG in serum is subject to hormonal regulation mainly by opposite effects of sexualsteroids on hepatocytes — estrogens activate, while androgens inhibit. Other hormones, such as thyroid hormones, are also strong activators of SHBG production.

In men, the SHBG concentration is 30–50% of the female concentration. In healthy men with an intact hypothalamic pituitary-gonadal axis, an increase in SHBG plasma levels leads to a short-term reduction in free testosterone while stimulating testosterone synthesis until normal levels are restored. Both an increase and a decrease in SHBG levels can be regulated by this feedback mechanism.

Fig. 2.15 Mechanisms by which steroid hormones can enter cells.

(a) The hormone diffuses freely across the cell membrane, binds to an intracellular receptor, and enters the nucleus to regulate gene expression. (b) Receptor-mediated endocytosis of steroid containing lipophilic molecules. The lipoprotein LDL binds its receptor and is taken up, degraded in lysosomes and the steroid cholesterol can enter different metabolic pathways. (c) Receptor-mediated endocytosis of steroids. The entire hormone-carrier is endocytotically bound after binding to a carrier protein. Following intracellular, the degradation of the carrier, the ligand hormone is released into the free cytoplasm. (d) Transport mediated uptake of molecules through the membrane. The steroid carrier is recognized by a membrane receptor and the ligand is transported into the cell.

Thread 'Role of SHBG in the free hormone hypothesis and the relevance of free testosterone in androgen physiology'

Oct 14, 2022

Role of sex hormone‑binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022)
N. Narinx · K. David1, · J. Walravens · P. Vermeersch · F. Claessens · T. Fiers · B. Lapauw · L. Antonio, · D. Vanderschueren

Keep in mind this is Fier's camp (cFTV).

Nothing new that those in the know were already well aware of!

You heard it here first the one and only Nelson's ExcelMale!

Abstract

According to the free hormone hypothesis, the biological activity of a certain hormone is best reflected by free rather...

Look over some of the threads in post # 6 regarding the binding T:SHBG/T:Albumin/T:Estradiol

Some critical points here!

* The bulk of T transportation is operated by three carriers: SHBG, CBG, and albumin, respectively, representing 44, 4 and 50% of the total T fraction in human male plasma [9]. While the vast majority of circulating T is protein-bound, on average only 2% circulates freely [9].

* The dynamic relationship between T and SHBG is characterized by their binding affinity, a measure of the strength of interaction between metabolite and carrier. Among steroid hormones, T has the second highest association constant (Ka), valued at 1–2 × 109 M−1 s−1, whereas DHT has the highest Ka for SHBG (2.69 × 109 M−1 s−1) [16]. Therefore, binding between T and SHBG occurs rapidly and is very strong with little tendency for spontaneous dissociation. Binding affinities of SHBG, and all other previously mentioned BPs, have been subject to extensive experimental research, summarized in Table 1 [9, 16].

* Albumin, designated as a non-specific transporter of T in the context of the free hormone hypothesis, is the most abundant protein in human plasma. It is a 66.5 kDa protein, circulating at a concentration of 35.0 to 50.0 g/L in both men and women, and is mainly responsible for maintaining colloid osmotic pressure [17]. It also plays a major role in the transportation and homeostasis of diverse ligands (electrolytes, fatty acids, hormones, vitamins, and drugs…) [18]. Synthesis of albumin only occurs in the liver, initiated by transcription of the ALB gene located on chromosome 4 (chr4q13.3) [19]. The binding affinity of T for albumin (Ka of±4× 104 M−1 s −1) is five orders of magnitude smaller and weaker than the binding affinity for SHBG. However, genetic variation in albumin could contribute to altered plasma albumin concentrations and/or binding affinity for T. To date, 71 genetic variants of albumin have been identified.

* Indeed, the albumin-bound fraction could, because of more probable spontaneous dissociation, potentially also have an effect on biological activity [21, 22]. Hence, the sum of the free and the albumin-bound fraction was determined to constitute the biologically available (or bioavailable) amount in circulation (Fig. 1). More recently, however, the interaction between the albumin-bound and free fraction has become even more complex. The binding dynamics of T to albumin have been generally believed to be in a 1:1 stoichiometric way. However, the structural location of the binding sites in albumin by two-dimensional nuclear magnetic resonance has shown that the carrier protein possesses at least three binding sites for T, each with its own association constant. Moreover, evidence has been provided that these binding sites are allosterically coupled and, importantly, shared with free fatty acids and some commonly used drugs, such as naproxen, warfarin, and exogenous glucocorticoids [23, 24]. Binding site competition and allosteric coupling can in certain conditions, especially postprandial and in circumstances of heightened levels of fatty acids and drug usage, result in displacement of T from its binding site thereby potentially affecting T bioavailability and/or metabolism [25, 26].

* All BPs, whether specific or non-specific, together control tissue availability and metabolic clearance rate of a given hormone through regulation of the free hormone fraction. In the free hormone hypothesis, it is mostly this free fraction, and by extension the free hormone concentration, that accounts for the biological activity of hormone action

* In what follows, we present in vitro and in vivo data, delivering arguments in favor of the free hormone hypothesis, emphasizing the importance of SHBG and the relevance of the determination of the non-protein-bound fraction. Hence, this review pitches the measurement of free T as an added value on top of total T.

SHBG and albumin define a delicate equilibrium in testosterone fractions

The bulk of T transportation is operated by three carriers: SHBG, CBG, and albumin, respectively, representing 44, 4 and 50% of the total T fraction in human male plasma [9]. While the vast majority of circulating T is protein-bound, on average only 2% circulates freely [9]. Human SHBG is a glycoprotein that is mainly produced by the liver. It circulates as a 90–100 kDa homodimeric protein and is able to bind all androgens and estrogens, with the exception of dehydroepiandrosterone sulfate (DHEAS) and androstenedione. Recent studies on UK biobank data indicated that the median plasma SHBG concentration is 36.89 nmol/L in men. In women, median SHBG plasma concentration was valued at 60.34 and 53.56 nmol/L for pre- and postmenopausal age, respectively [10, 11]. This carrier protein is encoded by the SHBG gene, found on the short arm (p12-13) of chromosome 17, consisting of eight exons [12]. Besides expression in the liver, the gene is also transcribed in the brain, uterus, breast, ovary, placenta, prostate, and testis [13]. The binding of sex steroid metabolites is accomplished in a binding pocket of the homodimeric protein, formed through the association of two monomers, stabilized by the bivalent cations zinc and calcium, with each homodimeric protein holding up to two molecules. A serine residue at position 42 in the binding pocket is responsible for the formation of hydrogen bonds with functional groups of T and estradiol [5, 14, 15]. The dynamic relationship between T and SHBG is characterized by their binding affinity, a measure of the strength of interaction between metabolite and carrier. Among steroid hormones, T has the second highest association constant (Ka), valued at 1–2 × 109 M−1 s−1, whereas DHT has the highest Ka for SHBG (2.69 × 109 M−1 s−1) [16]. Therefore, binding between T and SHBG occurs rapidly and is very strong with little tendency for spontaneous dissociation. Binding affinities of SHBG, and all other previously mentioned BPs, have been subject to extensive experimental research, summarized in Table 1 [9, 16].

Albumin, designated as a non-specific transporter of T in the context of the free hormone hypothesis, is the most abundant protein in human plasma. It is a 66.5 kDa protein, circulating at a concentration of 35.0 to 50.0 g/L in both men and women, and is mainly responsible for maintaining colloid osmotic pressure [17]. It also plays a major role in the transportation and homeostasis of diverse ligands (electrolytes, fatty acids, hormones, vitamins, and drugs…) [18]. Synthesis of albumin only occurs in the liver, initiated by transcription of the ALB gene located on chromosome 4 (chr4q13.3) [19]. The binding affinity of T for albumin (Ka of±4× 104 M−1 s −1) is five orders of magnitude smaller and weaker than the binding affinity for SHBG. However, genetic variation in albumin could contribute to altered plasma albumin concentrations and/or binding affinity for T. To date, 71 genetic variants of albumin have been identified. One of these albumin variants, Roma c.1033G > A, has been linked to reduced binding of T [20]. Lower binding affinity for albumin, which has also been demonstrated for all other steroid and thyroid hormones, has raised discussion about the relevance of this albumin-bound fraction. Indeed, the albumin-bound fraction could, because of more probable spontaneous dissociation, potentially also have an effect on biological activity [21, 22]. Hence, the sum of the free and the albumin-bound fraction was determined to constitute the biologically available (or bioavailable) amount in circulation (Fig. 1). More recently, however, the interaction between the albumin-bound and free fraction has become even more complex. The binding dynamics of T to albumin have been generally believed to be in a 1:1 stoichiometric way. However, the structural location of the binding sites in albumin by two-dimensional nuclear magnetic resonance has shown that the carrier protein possesses at least three binding sites for T, each with its own association constant. Moreover, evidence has been provided that these binding sites are allosterically coupled and, importantly, shared with free fatty acids and some commonly used drugs, such as naproxen, warfarin, and exogenous glucocorticoids [23, 24]. Binding site competition and allosteric coupling can in certain conditions, especially postprandial and in circumstances of heightened levels of fatty acids and drug usage, result in displacement of T from its binding site thereby potentially affecting T bioavailability and/or metabolism [25, 26].

The link between binding proteins and the free hormone hypothesis

All BPs, whether specific or non-specific, together control tissue availability and metabolic clearance rate of a given hormone through regulation of the free hormone fraction. In the free hormone hypothesis, it is mostly this free fraction, and by extension the free hormone concentration, that accounts for the biological activity of hormone action

Core support to the free hormone hypothesis: in vitro and in vivo data

Since its postulation by Mendel in 1989, the understanding of the free hormone hypothesis has advanced significantly. New insights could possibly contribute to the expertise of the daily management of many endocrine disorders. The clinical relevance and utility of this concept are determined by the relationship between the different fractions of the plasma hormone pool and the clinical manifestation of the corresponding affected endocrine axis. Currently, serum total T concentration is still most often used as the primary determinant for the assessment of androgen status in clinical practice. However, the consensus in the discussion on the most clinically useful measurement of sex steroids, total or free concentration, is yet to be reached [39]. In what follows, we present in vitro and in vivo data, delivering arguments in favor of the free hormone hypothesis, emphasizing the importance of SHBG and the relevance of the determination of the non-protein-bound fraction. Hence, this review pitches the measurement of free T as an added value on top of total T.

madman · 2025-04-13T10:59:15-0500

Again!

* All BPs, whether specific or non-specific, together control tissue availability and metabolic clearance rate of a given hormone through regulation of the free hormone fraction. In the free hormone hypothesis, it is mostly this free fraction, and by extension the free hormone concentration, that accounts for the biological activity of hormone action

Csd456 · 2025-04-14T02:53:43-0500

Cataceous said:
Your free testosterone isn't extremely low, so it's borderline whether you should be characterized as hypogonadal. Nonetheless, there are at least some suggestions that very high SHBG like yours may interfere with androgenic activity. Therefore I wouldn't condemn you for wanting to experiment. It's good that you have some awareness of the possible negative consequences of traditional TRT. Fortunately there are alternatives.

There are two options that might be called TRT-lite: either testosterone nasal gel (e.g. Natesto) or buccal testosterone troches. These are very fast acting forms of testosterone, meaning that after a dose serum testosterone does not stay elevated for more than a few hours. This allows your system to keep working normally, and generally preserves fertility. In contrast, traditional TRT is relatively long acting and usually results in complete HPTA suppression.

Another option is to use a SERM such as enclomiphene. This can be quite effective in improving free testosterone. However, there are mixed anecdotes concerning the subjective benefits.

If none of these options is practical for you then I'll throw out the unproven possibility that some forms of testosterone suspension may qualify as "short-acting", and thus could behave like nasal gel or buccal troches. The main drawback is that this requires two or three small injections daily. On the plus side, at least in the U.S. it is not difficult to obtain testosterone suspension.

Thank you very much for your detailed reply. I have a call today with a new clinic, so I can go in armed with some more info.

Systemlord said:
Quality of life is all that matters.

Agreed. Hence I’m pursuing this, but with a working system and a girlfriend that wants babies asap - it seems I should at least look into other options outside of TRT.

once again, appreciate all the lengthy replies. Some incredible detail.